1. Technical Field
The present invention relates to a method and apparatus for rapidly making, screening, and characterizing an array of materials in which process conditions are controlled and monitored, and in particular where the feed to each reactor vessel is continuously fed.
2. Discussion
Combinatorial materials science generally refers to methods for creating a collection of diverse compounds or materials using a relatively small set of precursors and/or methods for rapidly testing or screening the collection of compounds or materials for desirable performance characteristics and properties. As currently practiced, combinatorial materials science permits scientists to systematically explore the influence of structural variations in candidates by dramatically accelerating the rates at which they are created and evaluated. Compared to traditional discovery methods, combinatorial methods sharply reduce the costs associated with preparing and screening each candidate.
Combinatorial chemistry has revolutionized the process of drug discovery. See, for example, 29 Acc. Chem. Res. 1-170 (1996); 97 Chem. Rev. 349-509 (1997); S. Borman, Chem. Eng. News 43-62 (Feb. 24, 1997); A. M. Thayer, Chem. Eng. News 57-64 (Feb. 12, 1996); N. Terret, 1 Drug Discovery Today 402 (1996)). One can view drug discovery as a two-step process: acquiring candidate compounds through laboratory synthesis or through natural product collection, followed by evaluation or screening for efficacy. Pharmaceutical researchers have long used high-throughput screening (HTS) protocols to rapidly evaluate the therapeutic value of natural products and libraries of compounds synthesized and cataloged over many years. However, compared to HTS protocols, chemical synthesis has historically been a slow, arduous process. With the advent of combinatorial methods, scientists can now create large libraries of organic molecules at a pace on par with HTS protocols.
Recently, combinatorial approaches have been used for discovery programs unrelated to drugs. For example, some researchers have recognized that combinatorial strategies also offer promise for the discovery of inorganic compounds such as high-temperature superconductors, magnetoresistive materials, luminescent materials, and catalytic materials. See, for example, U.S. Pat. No. 5,776,359, as well as U.S. patent application Ser. No. 08/327,513 xe2x80x9cThe Combinatorial Synthesis of Novel Materialsxe2x80x9d (published as WO 96/11878) and co-pending U.S. patent application Ser. No. 08/898,715 xe2x80x9cCombinatorial Synthesis and Analysis of Organometallic Compounds and Catalystsxe2x80x9d (published as WO 98/03251), which are each herein incorporated by reference.
Because of its success in eliminating the synthesis bottleneck in drug discovery, many researchers have come to narrowly view combinatorial methods as tools for creating structural diversity. Few researchers have emphasized that, during synthesis, variations in temperature, pressure and other process conditions can strongly influence the properties of library members. For instance, reaction conditions are particularly important in formulation chemistry, where one combines a set of components under different reaction conditions or concentrations to determine their influence on product properties. Moreover, it is often beneficial to mimic industrial processes that are different than in pharmaceutical research so that many workers have failed to realize that processes often can be used to distinguish among library members. Some parallel reactors are known; see for example WO 98/36826 and U.S. Pat. Nos. 4,099,923 and 4,944,923, that are each incorporated herein by reference. However, what is needed is an apparatus for preparing and screening combinatorial libraries in which an industrial process can be followed.
The present invention provides a method and apparatus for reacting a plurality of different mixtures in parallel where one or more reactants are constantly fed to a plurality of reaction vessels from one or more sources. The present invention provides a method and apparatus for semi-continuous processes, in which one or more reagents is fed into the reactor from a source or header vessel. The present invention also provides a method and apparatus for continuous processes, in which product is simultaneously removed from the reactor as reagents are fed into the reactor. In addition to control of the reactants, catalysts, initiators, solvents, etc. chosen for a particular reaction, certain reaction conditions can be controlled including temperature, pressure, mixing, rate of reactant addition and/or rate of product removal.
Broadly, each reaction is contained within a reactor vessel, with a plurality of reactor vessels optionally being combined into a single parallel reactor block. Associated with each reactor vessel is one or more reactant sources (called xe2x80x9cheader barrelsxe2x80x9d) that provide one or more reactants that are fed into the reactor. A plurality of sources or header barrels can be provided in a header block. The header barrel is connected to the reactor vessels via a transfer line. A transfer system feeds reactant from the header barrel, through the transfer line and into the reactor vessel, optionally while the contents of the reactor are being mixed. The transfer system may comprise a pump or a plunger. The reactor vessel is typically sealed to the outside except for the connection to the transfer line, and methods of sealing are provided. In some embodiments, the entire system is sized to allow for the reactors, headers, plungers and drive system to fit into an inert atmosphere glove box, appropriate for air and moisture sensitive reactions.
In a much more specific embodiment, a 96-cell semi-continuous parallel reactor block is provided. Ideally, each vessel may be located at standard microtiter plate spacing. A separate header barrel is used for each reactor vessel and 96 header barrels are disposed in a header block. The reactor vessels within the reactor block are disposable glass vials, and the header barrels within the header block are glass syringes. The blocks and hence the reactor vessels are connected together with an inert orifice, which is the transfer line and also serves to thermally insulate the vessel from the barrel, as well as prevent undesired mixing of the contents of the two vessels. In this specific embodiment, the reactor vessel is constant volume, initially filled only partially with liquid, leaving a compressible gas headspace in the vessel. The header barrel""s volume is decreased throughout the reaction as the contents of the header are injected into the reactor, causing the pressure of the system gradually increase. Additional pressure rise is caused as the reactor vessels are heated, potentially above the boiling point of the liquids inside. Filling and assembly of the reactor/header reaction system may done in two halves, first by filling the reactor vessels to a desired amount and then filling the header barrels to a desired amount. The tops of the reactor vessels and header barrels are held in an array format by a collar, which leaves a portion of the bottom of each reactor vessel exposed. The reactor vessels are filled with different mixtures via a fluid-handling robot or manually. The collar is used to move all reactor vessels from a filling station into the reactor block at once. This allows the filling station to be independent of the reactor block, and also allows automated robotic handling and transfer of the reactors from one station to another. The header barrels are open at the end opposite the plunger rod. This allows the headers to be filled by direct dispensing (manual or automated), rather than by aspiration from another container. This ensures that the header vessel mixture is not altered in the event that the mixture is non-homogeneous. This open-end design also allows addition of mixing balls into the header, and reduces entrapment of gasses. Once the headers are filled, a plate containing individual orifices at each vessel position seals the entire array at once. The header barrels may be inverted and attached onto the reactor vessels. The orifices keep the header contents from spilling during the inversion, and are sized to keep the fluid velocity during injection much higher than the diffusion rate, keeping the contents of the header vessel separated from the reactor vessels during a reaction.
Heating of the reactor vessels and/or header barrels may be accomplished in many different ways. In the most specific embodiment, cartridge heaters mounted into the reactor block provide heating. Heat is conducted to the vessels axially through the block, then radially into the vessel. A temperature sensor is also mounted into the block to provide feedback for a closed-loop temperature controller. The same heating may be used in the header block.
In the preferred embodiment, sealing is accomplished by pressing the lip of the reactor vessel against a seal associated with a plate between the header and reactor blocks. However, a variety of sealing options are presented. Preferably, sealing is accomplished while accounting for a possible variation in the height of the reactor vessels, which may be removable vessels in wells of the reactor block. Thus, preferably both the reactor vessels and the header vessels are independently supported by a preloaded spring. This applies a virtually constant level of compression force during axial dimensional changes caused by vial height variations, seal compression set, differential thermal expansion of components, etc. A latch mechanism is also preferably used that translates a single input motion to two counter-rotating drums, which pull the plate carrying the orifices orthogonally onto the vessel lips without tilting. This mechanism may be actuated either manually, or automatically.
Mixing is optional, but may be accomplished by placing the entire reactor on a rocking platform, which allows mixing balls in each reactor vessel to tumble through the fluids, being pulled by gravity. Uniform stirring of all of the reactions can be obtained, which insures that any differences noted between reactions are not artifacts of the manner in which the samples were mixed. Alternative embodiments include use of stirring bars (either magnetic or mechanical) or mechanical stirring.